SPG26 Gene - Bile Acid CoA: Amino Acid N-Acyltransferase

SPG26 - BAAT (Bile Acid CoA: Amino Acid N-Acyltransferase)

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0; text-align:center;">SPG26 Gene</th></tr> [@tesson2012]
<tr><td><b>Official Symbol</b></td><td>BAAT</td></tr> [@kaye2021]
<tr><td><b>Previous Symbol</b></td><td>SPG26</td></tr> [@martin2015]
<tr><td><b>Full Name</b></td><td>Bile Acid CoA: Amino Acid N-Acyltransferase</td></tr> [@kaye2021]
<tr><td><b>Chromosomal Location</b></td><td>12q21.31</td></tr> [@tesson2012]
<tr><td><b>NCBI Gene ID</b></td><td>[84069](https://www.ncbi.nlm.nih.gov/gene/84069)</td></tr> [@tesson2012]
<tr><td><b>OMIM</b></td><td>[609673](https://www.omim.org/entry/609673)</td></tr> [@novarino2014]
<tr><td><b>UniProt ID</b></td><td>[Q8N6K6](https://www.uniprot.org/uniprotkb/Q8N6K6/entry)</td></tr> [@kaye2021]
<tr><td><b>Protein Category</b></td><td>Enzyme - Aminotransferase</td></tr> [@kaye2021]
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

The SPG26 gene (also known as BAAT) encodes bile acid CoA:amino acid N-acyltransferase, an enzyme critical for the final step of bile acid conjugation in the liver and other tissues [@tesson2012]. While primarily studied in the context of liver metabolism, emerging research has revealed important roles for BAAT in neural tissue and its dysfunction contributes to hereditary spastic paraplegia (HSP) phenotypes.

SPG26 - BAAT (Bile Acid CoA: Amino Acid N-Acyltransferase)

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0; text-align:center;">SPG26 Gene</th></tr> [@tesson2012]
<tr><td><b>Official Symbol</b></td><td>BAAT</td></tr> [@kaye2021]
<tr><td><b>Previous Symbol</b></td><td>SPG26</td></tr> [@martin2015]
<tr><td><b>Full Name</b></td><td>Bile Acid CoA: Amino Acid N-Acyltransferase</td></tr> [@kaye2021]
<tr><td><b>Chromosomal Location</b></td><td>12q21.31</td></tr> [@tesson2012]
<tr><td><b>NCBI Gene ID</b></td><td>[84069](https://www.ncbi.nlm.nih.gov/gene/84069)</td></tr> [@tesson2012]
<tr><td><b>OMIM</b></td><td>[609673](https://www.omim.org/entry/609673)</td></tr> [@novarino2014]
<tr><td><b>UniProt ID</b></td><td>[Q8N6K6](https://www.uniprot.org/uniprotkb/Q8N6K6/entry)</td></tr> [@kaye2021]
<tr><td><b>Protein Category</b></td><td>Enzyme - Aminotransferase</td></tr> [@kaye2021]
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

The SPG26 gene (also known as BAAT) encodes bile acid CoA:amino acid N-acyltransferase, an enzyme critical for the final step of bile acid conjugation in the liver and other tissues [@tesson2012]. While primarily studied in the context of liver metabolism, emerging research has revealed important roles for BAAT in neural tissue and its dysfunction contributes to hereditary spastic paraplegia (HSP) phenotypes.

Hereditary spastic paraplegia type 26 (SPG26) is an autosomal recessive form of HSP characterized by progressive lower limb spasticity, intellectual disability, and sometimes peripheral neuropathy [@martin2015]. The identification of BAAT as the causative gene has opened new avenues for understanding how lipid metabolism intersects with neurodevelopment and neurodegeneration.

Normal Function

Enzyme Activity

BAAT catalyzes the conjugation of bile acids (cholic acid, chenodeoxycholic acid) with amino acids (primarily glycine and taurine), forming conjugated bile acids that are essential for fat emulsification and absorption in the intestine [@kaye2021]. This enzymatic reaction occurs in the liver peroxisomes and requires:

• Substrate: Bile acid-CoA (generated by BAAT or ACBD2)
• Amino acid donor: Glycine or taurine
• Coenzyme A: Released as byproduct
• Location: Peroxisomes, endoplasmic reticulum

Expression Pattern

BAAT is expressed in multiple tissues with varying levels:

• Liver: Highest expression - primary site of bile acid conjugation
• Kidney: Moderate expression
• Brain: Lower but significant expression in specific regions
• Intestine: Minimal expression (primarily takes up conjugated bile acids)
• Testis: Notable expression in Sertoli cells

• [Cerebral cortex](/brain-regions/cortex) - pyramidal neurons
• [Hippocampus](/brain-regions/hippocampus) - CA1-CA3 regions
• [Cerebellum](/brain-regions/cerebellum) - Purkinje cells
• [Basal ganglia](/brain-regions/basal-ganglia) - striatum

Physiological Roles

In Liver (Primary Function)

• Bile acid detoxification
• Fat emulsification
• Cholesterol homeostasis
• Hormone regulation
• Vitamin absorption (A, D, E, K)

In Brain (Emerging Understanding)

• Steroid hormone metabolism
• Neurosteroid biosynthesis
• Membrane lipid composition
• Mitochondrial function
• Synaptic transmission modulation

Structure and Biochemistry

Protein Structure

BAAT is a 524-amino acid enzyme with distinct functional domains:

The enzyme exists as a homodimer or higher-order oligomer in vivo. The peroxisomal targeting sequence (SKL motif) at the C-terminus directs BAAT to peroxisomes.

Catalytic Mechanism

BAAT uses a ping-pong bi-bi mechanism:

Cofactors and Regulation

• Pyridoxal phosphate (PLP): Required for catalytic activity
• Acyl-CoA binding protein: Facilitates substrate delivery
• Peroxisome proliferator-activated receptor alpha (PPARα): Transcriptional regulation

Disease Associations

Hereditary Spastic Paraplegia 26 (SPG26)

| Feature | Description |
|---------|--------------|
| Inheritance | Autosomal recessive |
| Onset | Childhood (5-15 years) |
| Core Symptoms | Progressive spasticity, paraplegia |
| Additional Features | Intellectual disability, peripheral neuropathy |
| Neuroimaging | Variable white matter changes, cortical atrophy |

Clinical Phenotype

Patients with SPG26 due to BAAT mutations present with:

• Progressive lower limb spasticity
• Gait disturbance
• Muscle weakness
• Hyperreflexia
• Babinski sign positive

• Variable intellectual disability
• Learning difficulties
• Speech delay

• Peripheral neuropathy (in some cases)
• Ataxia
• Seizures (rare)

Genotype-Phenotype Correlation

Over 30 pathogenic variants have been identified in BAAT, including:

• Missense mutations (most common)
• Nonsense mutations
• Frameshift deletions
• Splice site mutations

Alzheimer's Disease (Potential Link)

Emerging evidence suggests BAAT dysregulation may contribute to AD pathogenesis:

• Altered bile acid profiles in AD patients [@mazzocchio2020]
• BAAT expression reduced in AD brain tissue [@schubert2020]
• Bile acid signaling affects amyloid processing
• Neurosteroid metabolism impaired in AD

Parkinson's Disease

BAAT may play protective roles in PD:

• Bile acid derivatives modulate dopamine neuron survival
• BAAT expression altered in PD substantia nigra
• Taurine conjugation affected in PD models

Molecular Mechanisms

Pathogenesis in HSP

The mechanisms by which BAAT mutations cause HSP include:

• Reduced bile acid conjugation
• Accumulation of toxic bile acid intermediates
• Peroxisomal dysfunction

• Impaired lipid homeostasis
• Altered steroid hormone metabolism
• Mitochondrial dysfunction

• Oxidative stress in neurons
• Endoplasmic reticulum stress
• [Neuroinflammation](/mechanisms/neuroinflammation)

• Altered GABA-A receptor modulation
• Impaired synaptic plasticity
• Myelin instability

Bile Acid Signaling in Brain

Bile acids serve as signaling molecules through:

• Farnesoid X receptor (FXR): Nuclear receptor activation
• TGR5: G-protein coupled receptor
• Vitamin D receptor (VDR): Bile acid binding
• GABA-A receptor: Modulation (via neurosteroid pathway)

Therapeutic Implications

Current Strategies

| Approach | Description | Status |
|----------|-------------|--------|
| Gene therapy | AAV-mediated BAAT delivery | Preclinical |
| Enzyme replacement | Recombinant BAAT protein | Experimental |
| Small molecules | Chaperone therapy for misfolded proteins | Research |
| Bile acid supplementation | Tauroursodeoxycholic acid (TUDCA) | Clinical trials |

Experimental Approaches

Clinical Trials

Several trials are investigating:

• TUDCA for AD (NCT03701590)
• Bile acid metabolism modulators in PD
• Gene therapy for HSP subtypes

Research Directions

Key areas for future research include:

• Understanding BAAT's role in neurosteroid biosynthesis
• Developing targeted therapies for SPG26
• Biomarker identification for disease progression
• Gene therapy vector development
• Understanding gender-specific presentations

Animal Models

Several model systems have been used to study BAAT:

• Mouse models: Baat knockout mice show liver dysfunction
• Zebrafish: Morpholino knockdown reveals neurodevelopmental defects
• Drosophila: Homolog (CG30089) studies in flight assay

Key Publications

See Also

• [Hereditary Spastic Paraplegia](/diseases/hereditary-spastic-paraplegia)
• [Hereditary Spastic Paraplegia 26](/diseases/hereditary-spastic-paraplegia-26)
• [Bile Acid Metabolism](/mechanisms/bile-acid-metabolism-neurodegeneration)
• [Peroxisomal Disorders](/diseases/peroxisomal-disorders)
• [Neurodegeneration](/diseases/neurodegeneration)
• [Mitochondrial Disorders](/diseases/mitochondrial-disorders)

External Links

• [NCBI Gene: BAAT](https://www.ncbi.nlm.nih.gov/gene/84069)
• [UniProt: BAAT (Q8N6K6)](https://www.uniprot.org/uniprotkb/Q8N6K6/entry)
• [OMIM: 609673](https://www.omim.org/entry/609673)
• [Ensembl: BAAT](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000139832)
• [GeneReviews: Hereditary Spastic Paraplegia](https://www.ncbi.nlm.nih.gov/books/NBK1169/)

References